Mesenchymal stem cells (MSCs) exert suppressive effects in several disease models including lupus prone mice. However, autologous MSC therapy has not been tested in human systemic lupus erythematosus (SLE). We evaluate the safety and efficacy of bone marrow (BM)-derived MSCs in two SLE patients; the suppressor effect of these cells in-vitro and the change in CD4+CD25+FoxP3+ T regulatory (Treg) cells in response to treatment. Two females (JQ and SA) of 19 and 25 years of age, fulfilling the 1997 American College of Rheumatology (ACR) criteria for SLE were infused with autologous BM-derived MSCs. Disease activity indexes and immunological parameters were assessed at baseline, 1, 2, 7 and 14 weeks. Peripheral blood lymphocyte (PBL) subsets and Treg cells were quantitated by flow cytometry, and MSCs tested for in-vitro suppression of activation and proliferation of normal PBLs. No adverse effects or change in disease activity indexes were noted during 14 weeks of follow-up, although circulating Treg cells increased markedly. Patient MSCs effectively suppressed in-vitro PBL function. However, JQ developed overt renal disease 4 months after infusion. MSC infusion was without adverse effects, but did not modify initial disease activity in spite of increasing CD4+CD25+FoxP3+ cell counts. One patient subsequently had a renal flare. We speculate that the suppressive effects of MSC-induced Treg cells might be dependent on a more inflammatory milieu, becoming clinically evident in patients with higher degrees of disease activity.
"Today, it is well accepted that MSCs have important immunosuppressive properties over the entire immune system , mainly exerting their effects on T, B, NK, and dendritic cells  . This immunomodulatory capacity of MSCs has opened new therapeutic prospects in the management of proinflammatory and autoimmune pathologies   . The therapeutic potential of MSCs has been demonstrated in a variety of autoimmune disease models including graftversus-host disease (GVDH) , experimental autoimmune encephalomyelitis (EAE)  , collagen-induced arthritis "
[Show abstract][Hide abstract] ABSTRACT: The Silences of the Archives, the Reknown of the Story.
The Martin Guerre affair has been told many times since Jean de Coras and Guillaume Lesueur published their stories in 1561. It is in many ways a perfect intrigue with uncanny resemblance, persuasive deception and a surprizing end when the two Martin stood face to face, memory to memory, before captivated judges and a guilty feeling Bertrande de Rols. The historian wanted to go beyond the known story in order to discover the world of the heroes. This research led to disappointments and surprizes as documents were discovered concerning the environment of Artigat’s inhabitants and bearing directly on the main characters thanks to notarial contracts. Along the way, study of the works of Coras and Lesueur took a new direction. Coming back to the affair a quarter century later did not result in finding new documents (some are perhaps still buried in Spanish archives), but by going back over her tracks, the historian could only be struck by the silences of the archives that refuse to reveal their secrets and, at the same time, by the possible openings they suggest, by the intuition that almost invisible threads link here and there characters and events.
Stem cell International 01/2015; 2015:1-14. DOI:10.1155/2015/140170 · 2.81 Impact Factor
"The FoxP3 expression and Treg function have been linked with hemoxygenase-1 (HO-1), which is implicated in the activation as well as induction and/or expansion of Tregs, as it is constitutively expressed in human peripheral blood Tregs but not in resting CD4+CD25− non-Tregs , , , , , , . Since HO-1 derived carbon monoxide can induce the DosR dormancy regulon in mycobacteria, leading to latency and survival of this organism inside the host granuloma, we hypothesized that such a situation could contribute to 20–30 times higher lifetime risk of developing active tuberculosis in HIV infected individuals. "
[Show abstract][Hide abstract] ABSTRACT: Understanding of the chronic immune activation, breakdown of immune defense and synergistic effect between HIV and Mycobacterium tuberculosis (Mtb) may provide essential information regarding key factors involved in the pathogenesis of HIV disease. In this study, we aimed to highlight a few of the immunological events that may influence and accelerate the progression of HIV disease in the presence of co-infecting Mtb. A cross-sectional study was performed on cohorts, including anti-tubercular therapy (ATT) naïve active pulmonary tuberculosis (PTB) patients, antiretroviral therapy (ART) naïve HIV-1 infected individuals at different stages of disease, ATT and ART naïve HIV-PTB co-infected individuals and healthy controls. A significantly higher T-regulatory cell (Treg) frequency coupled with the high FoxP3 expression in the CD4 T-cells indicated an immunosuppressive environment in the advance stage of HIV-1 infection. This is further substantiated by high HO-1 expression favoring TB co-infection. Functionally, this change in Treg frequency in HIV-1 infected individuals correlated well with suppression of T-cell proliferation. Mtb infection seems to facilitate the expansion of the Treg pool along with increased expression of FoxP3, specifically the variant-1, as evident from the data in HIV-1 co-infected as well as in patients with only PTB. A significantly lower expression of HO-1 in co-infected individuals compared to patients with only HIV-infection having comparable CD4 count correlated well with increased expression of CCR5 and CxCR4 as well as NF-κB and inflammatory cytokines IL-6 and TNF-α, which collectively may contribute to enhanced viral replication and increased cell death, hence faster disease progression in co-infected individuals.
PLoS ONE 09/2014; 9(9):e106815. DOI:10.1371/journal.pone.0106815 · 3.23 Impact Factor
"However, studies performed on patients of autoimmune diseases have demonstrated the advantage of using allogeneic MSC. The Using of autologous MSC did not seem to improve SLE disease course despite an increase of proportion of peripheral blood T-regs.86 MSC extracted from SLE patients grew slower in culture, display less viability and produce less TGF-β in contrast to allogeneic healthy MSC indicating that the former cells are probably defective in function.87 "
[Show abstract][Hide abstract] ABSTRACT: The vast majority of literature pertaining to mesenchymal stem cells (MSC) immunomodulation has focussed on bone marrow derived MSC that are systemically infused to alleviate inflammatory conditions. Rheumatoid arthritis (RA) is the commonest autoimmune joint disease that has witnessed significant therapeutic advances in the past decade, but remains stubbornly difficult to treat in a subset of cases. Preclinical research has demonstrated that bone marrow, adipose, synovial and umbilical cord derived MSC all suppress the functions of different immune cells thus raising the possibility of new therapies for autoimmune diseases including RA. Indeed, preliminary evidence for MSC efficacy has been reported in some cases of RA and Systemic Lupus Erythromatosis (SLE). The potential use of BM-MSC for RA therapy is emerging but the use of synovial MSC (S-MSC) to suppress the exaggerated immune response within the inflamed joints remains rudimentary. Synovial fibroblasts that are likely derived from S-MSCs, also give rise to a cell cultured progeny termed fibroblast like synoviocytes (FLS), which are key players in the perpetuation of joint inflammation and destruction. A better understanding of the link between these cells and their biology could be a key to developing novel MSC based strategies for therapy. The review briefly focuses on BM-MSC and gives particular attention to joint niche synovial MSC and FLS with respect to immunoregulatory potential therapy roles.
QJM: monthly journal of the Association of Physicians 02/2014; 107(7). DOI:10.1093/qjmed/hcu033 · 2.50 Impact Factor
Holger Hackstein, Anne Lippitsch, Philipp Krug, Inna Schevtschenko, Sabine Kranz, Matthias Hecker, Kristina Dietert, Achim D. Gruber, Gregor Bein, Cornelia Brendel, Nelli Baal
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